Synthesis of Substituted Phenoxyacetic Acids

Solvent-free synthesis of substituted phenoxyacetic acids (77) with substituted phenols and chloroacetic acid was carried out under microwave irradiation by Nagy et al. (1997). 2-Chlorophenol reacted with ethanol in the presence of sodium hydroxide and a phase transfer catalyst under microwave irradiation to give 2-ethoxyphenol (78) conveniently within a few minutes (Pang et al., 1996). 

Nagy, G., FUip, S.V., Surducan, E., and Surducan, V. 1997. Solvent-free synthesis of substituted phenoxyacetic acids under microwave irradiation. Synthetic Communications, 27 3729-36. 

Synthesis of Substituted Phenoxyacetic Acids M4 and Substituted Phenoxyacetyl Chlorides MS... 

Scheme 9.4 Synthesis of substituted phenoxyacetic acids M4 (Method M4-A)...

In addition to the examples of coumarin syntheses given in the reviews mentioned above and in the treatise on heterocyclic compounds (B-51MI22400), more recent studies have made use of the Perkin synthesis. These include the use of substituted phenoxyacetic acids to prepare 3-phenoxycoumarins (78CI(L)628> and the synthesis of chlorocoumarins from chlorosalicylaldehydes (81T2613). The use of DBU in place of sodium acetate was necessary to effect the ring closure of a number of o-hydroxyketones (78BCJ1907). 

The method for preparations of substituted phenoxyacetic acids M4 and substituted phenoxyacetyl chlorides MS has been discussed in Sect. 2.1.3. MS were prepared from corresponding substituted phenoxyacetic acids M4. M4-1-M4-3, M4-6-M4-8, and M4-9-M4-14 which were used to prepare IGr-U are shown in Table 2.7. M4 could be prepared according to the general synthesis procedure of M4 in Sect. 9.1.5. 

The synthetic yields of lA-IF using the method of route (2) were better than that of route (1). Therefore, we mainly chose the synthetic route (2) to obtain lA-IF. O, 0-DiaIkyl 1-hydroxyaIkylphosphonates M2, substituted phenoxyacetic acids M4 and substituted phenoxyacetyl chlorides M5 are the important intermediates for the synthesis of lA-IF. The preparation of M2, M4 and M5 is described in Sects. 2.1.2 and 2.1.3, respectively. 

Scheme 2.8 Synthesis of fluoro and trifluoromethyl-substituted phenoxyacetic acids M4...

Alkali metal salts of 0-alkyl 1-(substituted phenoxyacetoxy)alkylphosphonic acids IIA-IIE could be easily synthesized by the reaction of (9,(9-dialkyl 1-(substituted phenoxyacetoxy)alkylphosphonates lA or IC with corresponding lithium bromide, sodium iodide, or potassium iodide in refluxing acetone. The synthetic route of IIA-IIE is shown in Scheme 3.5. For the synthesis of IIA-IIE, 1-hydrox-yalkylphosphonates M2, substituted phenoxyacetyl chloride MS, and 0,(9-dialkyl 1-(substituted phenoxyacetoxy)alkylphosphonates lA or IC could be prepared according to the known methods as stated in Chap. 2. 0,0-Dialkyl phosphonate Ml was used directly as obtained commercially or prepared by the reaction of phosphorus trichloride and methanol. Ml reacted with different aldehydes to give 0,0-diaUtyl 1-hydroxyalkylphosphonates M2. The substituted phenoxyacetic acids M4 were prepared in satisfactory yields by the reaction of corresponding substituted phenols with 2-chloroacetic acid or ethyl 2-bromoacetate followed by hydrolysis. The substituted phenoxyacetyl chlorides M5 could be easily obtained by the treatment of M4 with excess thionyl chloride. M2 reacted with MS to provide lA or IC (Scheme 3.5). 

Penicillin Formation by Penicillium Chrysogenum. The first reactions of the penicillin biosynthetic pathway are identical to the ones in A. chrysogenum (Figure 1.1-1). IPN, however, is not epimerized to penicillin N instead it is converted to 6-aminopenicillanic acid (6-APA) by removal of the L-a-aminoadipic acid side chain, which is substituted by a hydrophobic acyl group. Both steps are catalyzed by the same enzyme, the acyl coenzyme A IPN acyltransferase (IAT). The enzymatic activity of lAT is believed to be the result of the processing of a 40-kD monomeric precursor into a dimeric form consisting of two subunits with MWs of 11 and 29 kD. Due to the broad substrate specifity of lAT, various penicillin derivatives are synthesized naturally by attachment of different acyl-CoA derivatives to the 6-APA-core. For industrial purposes, to facilitate extraction by organic solvents, synthesis usually is directed to the less hydrophilic penicillin V or penicillin G. This is by addition of phenoxyacetic acid or phenylacetic acid, respectively, as precursors to the culture broth. 

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